Steroidal delta**16-20(alpha and beta)-hydroperoxide 21-ethers



United States Patent 0 US. Cl. 260-43955 20 Claims ABSTRACT OF THE DISCLOSURE A process for the production of A -20-keto-2l-hydroxy steroids. The process involves reacting a A -21-hydroxy steroid with a vinyl ether to give the corresponding saturated ether, photosensitized oxidation yields the A -20 (a and ,8) hydroperoxides which are converted to the A -20-keto-2l-hydroXy-2lethers followed by hydrolysis to yield the A -20-keto-21-hydroxy steroids. The compounds are useful as intermediates and as anti-inflammatory agents.

This invention relates to (1) the reaction of A 21-hydroxy steroids (1) with vinyl ethers to produce the corresponding saturated ethers (II), (2) the photosensitized oxygenation of these (II) to yield the corresponding A -20 (a and B) hydroperoxides (III), (3) the conversion of these (HI) to the corresponding steroidal A -20-keto- 21-hydroXy-2l-ethers (IV) and finally (4) the hydrolysis of the compounds of Formula IV to give the corresponding valuable A -20-keto-2l-hydroxy steroids (V).

The novel compounds of this invention and processes for the preparation thereof are illustratively represented by the following sequence of formulae wherein the Roman numerals therebeneath correspond with those above:

H OH

and R 0 wherein R is selected from the group consisting of alkyl, haloalkyl, nitroalkyl, alkenyl, cycloalkyl, aryl, aralkyl, haloaryl, haloaralkyl and nitroaryl of from 1 to 24 atoms, inclusive, and R R and R have the same meaning as R and in addition hydrogen; V is selected from the group consisting of hydrogen and hydroxyl, with the proviso that V is not present when the 4(5)-carbon atom linkage is a double bond; W is selected from the group consisting of hydrogen, methyl, chlorine and fluorine; Y is selected from the group consisting of the a-hydroxymethylene radical the ,B-hydroxymethylene radical on c the a-acyloxyniethylene radical wherein Ac is the acyl radical of an organic carboxylic acid containing from one to twelve carbon atoms, inclusive, the 3-acyloxymethylene radical OAc wherein Ac has the same meaning as above, the acyloxymethylidyne radical COAc) wherein Ac has the same meaning as above, the alkoxymethylidyne radical (BC-OR) wherein R is a lower-alkyl radical of from one to six carbon atoms, inclusive, the carbonyl radical C=O) and an alkylene ketal radical of the formula O(CII:),, R C C O(CH:)n \R' wherein n is selected from the group consisting of zero and the integers one and two and R is selected from the group consisting of hydrogen and a loweralkyl radical containing from one to six carbon atoms, inclusive; when Y is a carbonyl radical, the 1(2), 4(5), 6(7) and 9(11)- carbon atom linkages are selected from the group consisting of single and double bonds; when Y is other than a carbonyl radical, the 1(2), 3(4), 4(5), 5(6), 6(7) and 9(11)-carbon atom linkages are selected from the group consisting of single and double bonds; Z is selected from the group consisting of the methylene radical CH the a-hydroxymethylene radical, the B-hydroxymethylene radical, the carbonyl radical and when W is selected from the group consisting of chlorine and fluorine, Z is additionally selected from the group consisting of chloromethylene and fluoromethylene; Z and W at the 9-position together constitute a 9( l l )-tlOUbiC bond.

Cit

The novel compounds of this invention embraced by Formulae II, III, IV and V of the above flow-sheet possess valuable pharmacological properties, particularly antiinflammatory activity. This property renders them useful in the treatment of various inflammatory conditions of the skin, eyes, respiratory tract, bones and internal organs due to viral or bacterial infections, contact dermatitis, allergic reactions and rheumatoid arthritis. The compounds of the aforesaid formulae are also useful as intermediates in the preparation of a wide variety of physiologically highly active and therapeutically valuable anti-inflammatory compounds substituted at the 16-position of the steroid nucleus, e.g., the appropriate A -20-ketones cmbraced by Formula V, derived from the corresponding steroids of Formula IV, can be conveniently converted by known methods to highly effective anti-inflammatory medicaments such as 9a-fiuoro-llfl, 16a, 17a, 2l-tetrahydroxy-1,4-pregnadiene-3,20-dione (triamcinolone) and its corresponding 6a-fiuoro analogue, i.e., as disclosed in J. Amer. Chem. Soc. 78, 5693 (1956) and ibid. 82, 3399 (1960), respectively. The latter is especially valuable where long-term anti-inflammatory therapy is necessary, inasmuch as its calcium sparing property prevents depleting the bones of calcium and consequently avoids osteoporosis which results from continued administration of certain other commonly employed corticoids.

The compounds of the present invention can be prepared and administered to mammals, birds, humans and animals in a wide variety of oral and parenteral dosage forms, singly or in a mixture with other coacting compounds. They can be associated with a carrier which can be a solid material or liquid, in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, or the like, preferably in unit dosage forms for simple administration of precise dosage.

Steroidal A -2O ketones are usually obtained from plant sapogenins (see Fieser and Fieser, Steroids, page 547 et seq., Reinhold, New York, 1959), making them readily available, but at a very early and not necessarily convenient stage in cortical synthesis. For many purposes, it would be desirable to be able to introduce the A -20-keto system much later in the synthetic scheme; also it would be advantageous to be independent of plant source for these intermediates, i.e., those embraced by Formula V. Dehydration of 17a-hydroxy-20-keto-steroids or their ketone derivatives (such as semi-carbazones) has been carried out by several methods, e.g., J. Amer. Chem. Soc. 78, 5693 (1956); ibid. 77, 1028 (1955); ibid. 75, 4830 (1953); US. Pat. 3,082,219; South African application No. 5054/59. However, the yields obtained in employing these processes are usually poor in comparison with those of the present process.

As indicated in the flow-sheet above, the compounds of Formula IV can be prepared (1) directly from the corresponding 21-ethers (II) by a one-pot process, or (2) by dehydration of the isolated hydroperoxy 2l-ethers (III) resulting from the photosensitized oxygenation of the compounds of Formula II. Hydrolysis of the A -2O-kcto 2lethers (IV) gives the corresponding A -20-keto-2l-hydroxy steroids (V). When the A -20-keto 2l-ethers (IV) are prepared directly from the N -steroidal 21-ethers (II), the A -20-hydroperoxides (III) are not separated from the reaction mixture, but a suitable dehydrating agent is added thereto and after an appropriate period of time has elapsed to permit the reaction to be completed, the compounds of Formula IV are recovered. Alternatively, the dehydrating agent can be added to the reaction mixture at the start of the photooxygenation along with the reagents necessary for said step. This procedure permits rearrangement of the hydroperoxides (III) in si'.u as they are being formed to yield the corresponding A 20-keto 21-ethers (IV). An additional advantage of the novel process is that the ether protecting group at C-2l produces a more favorable ratio in the photoscusitizctl oxygenation between the desired hydroperoxy 21-ethers (III) and the undesired by-products of the formula are (a) A -21-HYDROXY STEROIDAL OLEFINS (1) CORRESPONDING ZI-ETHERS (II) In carrying out this step of the process, a compound of Formula I is treated with an ether having a vinylene O=C group in the presence of an acid, e.g., sulfuric acid, p-toluenesulfonic acid, pyridine hydrochloride,

-etc. Both the cis and trans compounds of Formula I are reactive. Numerous vinyl ethers, many of which are commercially available, can be employed; for example, those set forth in Example 7, below. This reaction can be carried out, preferably in an inert organic solvent, at a wide range of temperatures, e.g., below the boiling point of the solvent and the ether.

(b) PHOTOSENSITIZED OXYGENATION OF A STEROIDAL 21-ETHERS (II) A -(a AND 8)- HYDROPEROXIDE 21-ETHERS (III) The preferred photosensitizer is hematoporphyrin, but dyes such as the eosins, methylene blue and Rose Bengal have been found satisfactory. Advantageously, the light employed is a conventional fluorescent lamp surrounded by a glass jacket containing the steroid solution. Such an arrangement can be modified and adapted to provide a continuous flow process for large scale conversions; e.g., in vessels of large volume, irradiation can be accom plished by inserting the fluorescent lamp into glass wells or positioning them against glass ports. However, the process of the invention is not limited to the use of this particular light source. Thus, any light source producing radiation in the region of maximum absorption of the photosensitizer can be used; for example, hematoporphyrin having maximum absorption at 377 mu, Rose Bengal at 340 and 550 m and Eosin Y at 328 and 515 m can all be satisfactorily employed with a fluorescent lamp as a light source. Sun light can also be used for this purpose, as well as incandescent lamps and carbon arc lights.

The preferred solvents are acetone, pyridine, methylene chloride, ethyl acetate, and dimethylformamide; organic bases, such as picolines and collidines, are also satisfactory. Inert solvents such as benzene and ethanol can also be used.

The optimum temperature for the photosensitized oxygenation of the starting steroid (I) was found to be be- 6 tween about 0 C. to about 40 C., but temperatures between about 100 C. and about C. are also satisfactory.

The time required for conversion of the compounds of Formula II to the corresponding 20 (a and EU-hydroperoxides (III) by the photosensitized oxygenation reaction depends on such factors as, light intensity, the rate of oxygen bubbling through the reaction mixture, the amount of photosensitizer present and the amount of substrate (II). Oxygen is usually bubbled through the reaction mixture throughout the course of the conversion; air can also be 'used. Pressure vessels charged with oxy gen and illuminated either from within or through glass ports can also be used. The progress of the reaction is followed by taking aliquots for thin-layer chromatography and terminating the reaction when starting material (II) is mainly converted to the hydroperoxide (III). The extent of the conversion can also be assessed by titration of the hydroperoxide formed, or by measuring the absorption of oxygen in a closed system. The time necessary to complete the photooxygenation is between about 1 and 24 hours. Both the cis and trans compounds of Formula II are reactive.

Isolated double bonds in the steroid starting material other than at the l7(20)-position, if not conjugated with a keto group, are also amenable to the photosensitized oxygenation reaction productive of their corresponding hydroperoxides. For example, by utilizing the procedures disclosed above, the A A A A A A A A A A A and A -bonds are susceptible to this conversion.

(c) DEHYDRATION OF A -20 (0: AND ED-HYDRO- PEROXIDE ZI-ETHERS (III) CORRESPONDING A16-20-KETO ZI-ETHERS IV This step is accomplished by employing usual acylating conditions. Dissolving the hydroperoxide 21-ethers (III) in acetic anhydride and pyridine and allowing the reaction mixture to stand at room temperature for a peroid of about 15 hours, or warming for a short time on a steam bath, readily yields the corresponding A -20- keto 21-ether (IV). Additional acylating agents can be used, e.g., acyl anhydrides other than acetic anhydride, acid chlorides and sulfonyl chlorides such as p-toluenesulfonyl chloride. Tertiary organic bases other than pyridine can be utilized, e.g., collidines and triethylamine. Bases such as sodium hydroxide and piperidine are also effective in converting the hydroperoxide 21- ether (III) to its A -20-keto 21-ether (IV).

(d) CONVERSION OF A -STEROIDAL 2l- ETH ERS (II) CORRESPONDING A 20 KETO ZI-ETHERS (IV) [WITHOUT ISOLATION OF A -20 (0c AND }3)-HYDROPEROXDE 21 ETHERS The two steps of the above process of this invention, namely, (b) the photosensitized oxygenation of the N steroidal 2l-ethers (TI) and (0) conversion by dehydration of the resulting intermediate hydroperoxide 21-ethers (III) to the corresponding A -2O-keto 21- ethers (IV), can be effected without isolating the hydroperoxide Zl-ethers (III). Thus, acetic anhydride or one of the acylating agents disclosed in (c), above, is added directly to the pyridine solution containing the intermediate A -20-hydroperoxide 2l-ether (III) resulting from irradiation and oxygenation of the starting [3 steroidal 2l-ether (II), and after standing at room temperature about 1 to 15 hours or warming on the steam bath the A -20-keto 21-ether product is isolated, as described in Example 15, below. Alternatively, the dehydrating agent can be added to the reaction mixture at the start of the photooxygenation, as in Example 9, below.

(e) HYDROLYSIS OF A -20-KETO 2l-ETHERS (IV) CORRESPONDING A 20 KETO 21- HYDROXY STEROIDS (V) The final step of the process involves the hydrolysis of a compound of Formula IV to yield the corresponding 21-hydroxy compound (V) The 21-ether (IV) is dissolved in an alkanol such as methanol and an acid, e.g., p-toluenesulfonic acid, hydrochloric acid and the like added; after standing at about room temperature for between about 0.5 to about 24 hours, followed by the addition of a base (e.g., diethylamine), the 21-hydroxy steroid (V) is isolated and purified by conventional procedures.

All of the compounds embraced by Formulae II, III, IV and V can be isolated from their reaction mixtures by conventional means, for example, when a water-miscible solvent is used, by pouring the reaction mixture into water and separating the resulting precipitate by filtration or by extraction with water-immiscible solvents. Additional purification of the product can be accomplished by conventional means, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, methanol, dilute methanol, ethanol, ether, methylene chloride and Skellysolve B (hexanes), mixtures and combinations of these solvents; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as methylene chloride- Skellysolve B, acetone-Skellysolve B, and the like.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described herein as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

Example 1.-1113,21-dihydroxy-4,17(20)-cis-pregnadien- 3-one 21-tetrahydropyranyl ether (II) A slurry of 50 g. (151 mmoles) of 115,21-dihydrxy- 4,17()-cis-pregnadien-3-one (I) in 150 ml. (1.64 moles) of 2,3-dihydropyran and 20 ml. of methylene chloride containing 200 mg. of pyridine hydrochloride was stirred at about 50 C. After about one hour the solids had dissolved and the solution was kept at room temperature for about 16 hours. Thin layer chromatography (TLC) of this material dissolved in 50% ethyl acetate and 50% Skellysolve B (hexanes) applied to silica gel (silicic acid) and developed with a mixture of 50% ethyl acetate and 50% Skellysolve B indicated that only traces of the starting material (I) remained. The reaction was stopped by the addition of 2 ml. of diethylamine and the reaction mixture concentrated in vacuo at 50 C. to constant weight to give 75.7 g. (121%) of crude product (II) with a melting point of 104 to 121 C. A pure sample of this crude material (II) was obtained by recrystallization from acetone; this sample of 11fl,21-dihydroxy-4,17(20)- cis-pregnadien-3-one ZI-tetrahydropyranyl ether (II) melted at 135.5 to 138 C. and its mobility by TLC was identical to that of an authentic sampling melting at 127.5 to 130 C. Infrared (IR) and nuclear magnetic resonance (NMR) spectra were consistent with the proposed structure.

Example 2.-115,2l-dihydroxy-4,l7(20)-cis-pregnadien- 3-one 2l-tetrahydropyranyl ether (II) A slurry of 50 g. (151 mmoles) of 115,21-dihydroxy- 4,17(20)-cis-pregnadien-3-one (I) in 250 ml. of dry tetrahydrofuran containing 60 g. (713 mmoles) of 2,3-dihydropyran and 40 mg. of p-toluenesulfonic acid was stirred at 25 C. for about 2 hours. Since the reaction was progressing slowly, the temperature was increased to about C. After stirring for about 1 hour, TLC indicated that the reaction was complete. About 50 mg. of triethylencdiumin was added and the solution concentrated in vacuo. The high boiling residue was dissolved in 250 ml. of benzene and the solution washed with water. The organic layer was concentrated in vacuo to give a crude product as an oil which gradually solidified. The solid material was dried to constant weight to yield 53.8 g. of crude 11fi,2l-dihydroxy-4,17(20)-cis-pregnadiene-3- one ZI-tetrahydropyranyl ether (II), having a melting point of 116 to 133 C.

Example 3.115,21-dihydroxy-4,17(20)-cis-pregnadien- 3-one 21-(1-isobutoxyethyl)ether (II) To a stirred slurry of g. of 115,21-dihydroxy- 4,17(20)-cis-pregnadien-3-one (I) in 100 ml. of tetrahydrofuran and 100 ml. of isobutyl vinyl ether, mg. of p-toluenesulfonic acid monohydrate was added. The mixture was maintained initially at 25 C., but since it appeared to be reacting slowly the temperature was raised to 35 C. After 7 minutes of stirring at this temperature all of the starting material had dissolved; after 1 hour of additional stirring the reaction was stopped by the addition of 1 ml. of pyridine. The reaction mixture was added to 500 ml. of benzene and the resulting solution washed with 5% sodium bicarbonate solution followed by several water washings. The organic layer was concentrated in vacuo to constant weight to give 1113,2l-dihydroxy- 4,l7(20)-cis-pregnadien 3 one 2l-(1'-isobutoxyethyl)ether (II). Attempts to obtain a crystalline product failed.

Example 4.1l5,21-dihydroxy-4,17(20)-cis-pregnadien- 3-one 21-( l'-methoxyethyl)ether(II) To a stirred slurry of 3.3 g. of 115,21-dihydroxy- 4,17(20)-cis-pregnadien-3-one (I) in 15 ml. of methylene chloride at 0 C., 5.81 g. of methyl vinyl ether and 50 mg. of pyridine hydrochloride was added. The temperature was increased to 35 C. and maintained there at for about 3 hours, at which time TLC showed th reaction was nearly complete. The reaction mixture was allowed to stand at room temperature for about 16 hours. About 0.3 ml. of pyridine was added to the reaction mixture which was then concentrated to a thick slurry. Crystallization of the solids from acetone gave 2.21 g. of 115,21- dihydroxy-4,17(20)-cis-pregnadien-3-one 2l-( 1'-methoxyethyl)ether (II) with a melting point of 157 to 162 C. The NMR spectrum of this product showed a characteristic methyl doublet at 5:1.30 and a methoxyl at 6:3.31 p.p.m. thus confirming the proposed structure of the product.

Example 5.115,21-dihydroxy-4,17(20)-cis-pregnadien- 3-one 21-(1'-methoxy-l-methylethyl)ether (II) To a stirred slurry of 5 g. of 11[5,21-dihydroxy-4,l7(20)- cis-pregnadien-3-one (I) in 30 ml. of acetone dimethyl ketal and 20 ml. of dry tetrahydrofuran, 5 mg. of ptoluenesulfonic acid was added. After stirring at room temperature for about 1 hour, the reaction was halted by the addition of 0.2 ml. of triethylamine. The solution was concentrated in vacuo at 15 C. to a volume of about 20 ml. Addition of 25 ml. of methanol and collection of the solids by filtration gave 4.23 g. yield) of product (II) melting at 161 to 165 C. Recrystallization from methanol raised the melting point of the product, 11fi,21- dihydroxy-4,17(20)-cis-pregnadien-3-one 21-(1'-methoxy- 1'-methylethyl)ether (II) to 164.5 to C.;

Analysis.Calcd. for C H O (percent): C, 74.59; H, 9.52. Found (percent): C, 74.34; H, 9.23.

Example 6.-1lfl,21-dihydroxy-4,17(20)-cis-pregnadien- 3-one Zl-tetrahydrofuranyl ether (11) Following the procedure of Example 1 but substituting 2,3-dihydrofuran for 2,3-dihydropyran, yields 1l/i,2l-dihydroxy-4,l7(20)-cis-pregnadien 3 one 2l-tetrahydrol'uranyl ether (ll).

Example 7.--21-ethers of 11,8,21-dihydroxy-4,17(20)- cis-pregnadien-3-one (II) Following the procedures of Examples 1 through 6 but substituting for the vinyl ethers employed therein the following:

( 1) phenyl vinyl ether,

(2) benzyl 2-brornopropenyl ether,

( 3) benzyl vinyl ether,

( 4) Z-bromovinyl methyl ether,

( 5) l-bromovinyl ethyl ether,

( 6) 2-bromovinyl ethyl ether,

(7) 2-bromovinyl o-tolyl ether,

(8) 2-bromovinyl phenyl ether,

(9) 2-butyloctyl vinyl ether,

(10) butyl l-phenylvinyl ether,

(1 1 p-t-butylphenyl vinyl ether,

(12) butyl l-propylvinyl ether,

( 13 l-butylvinyl ethyl ether,

( 14) l-butylvinyl methyl ether,

(15) 2-chloroethyl vinyl ether,

(16) 2-chloro-1,2-difluorovinyl phenyl ether,

(17) 2-chloro-1,Z-difiuorovinyl propyl ether,

('18) 2-chloro-1,2-difluorovinyl 2,2,3,3 -tetrafluoropropyl ether,

(19) 2-chloro-l-fiuorovinyl ethyl ether,

(20) 2-chlorovinyl ethyl ether,

(21) 2-chlorovinyl isopropyl ether,

(22) cyclohexylmethyl vinyl ether,

(23) cyclohexyl vinyl ether,

(24) 2,2-dichloro-l-fluorovinyl methyl ether,

(25) 2,2-dichloro-l-fluorovinyl phenyl ether,

(26) 2,2-dichloro-1-fiuorovinyl 2,2,2-trifluoroethyl ether,

(27) 2,4-dichlorophenyl vinyl ether,

(28) 1,2-dichlorovinyl ethyl ether,

(29) 2,2-dimethylpentyl vinyl ether,

(30) biphenyl vinyl ether,

(31) 2,2-diphenylvinyl methyl ether,

(32) docosyl vinyl ether,

(3 3 dodecyl vinyl ether,

(34) eicosyl vinyl ether,

(3 5) ethyl l-ethylvinyl ether,

(36) ethyl vinyl ether,

(37) ethyl 1-fluoro-2,2-diphenylvinyl ether,

(38) 2-ethylhexyl vinyl ether,

(3 9 ethyl-l-isopentyl vinyl ether,

ethyl-l-phenylvinyl ether,

0, m, and p-ethylphenyl vinyl ether,

1- (pethylphenyl) vinyl methyl ether,

(43) ethyl l-propyl'vinyl ether,

( 44) ethyl 2- (2,6,6-trimethyl-1-cyc1ohexen41-yl vinyl ether,

(45) ethyl triphenylvinyl ether,

(46) ethyl 1-vinyl-1,2-butadienyl ether,

(47) ethyl l-vinylpropenyl ether,

(48) ethynyl vinyl ether,

(49) l-fluorovinyl 2,2,2-trifluoroethyl ether,

( 50) heptyl vinyl ether,

(51) hexadecyl vinyl ether,

(5 2) hexyl vinyl ether,

(5 3 p-isohexylphenyl vinyl ether,

(54) isohexyl vinyl ether,

(5 5) isooctyl vinyl ether,

(5 6 isopentyl vinyl ether,

(57 isopentyl (and p) -vinylphenyl ether,

( 8) isopropyl vinyl ether,

(5 9) p-menth-1-en-8-ylvinyl ether,

(60) p-menth-2-yl vinyl ether,

( 61) p-menth-3 -y1 vinyl ether,

(62) 2-methylalkyl vinyl ether,

(63) I-methyI-Z-hutyryl vinyl ether,

(64) l-methylbutyl vinyl ether,

(65 p-6-methylheptylphenyl vinyl ether,

(66) l-rnethyl-Z-hexenyl vinyl ether,

(67 methyl 1-( p-nitrophenyl) vinyl ether,

(68) Z-methyl-Z-nitropropyl vinyl ether,

(69) Z-methyloctyl vinyl ether,

(70) p-methylphenethyl vinyl ether,

(71) methyl l-phenylvinyl ether,

(72) methyl l-propyl-vinyl ether,

(73) methyl l-p-tolylvinyl ether,

(74) methyl l-vinylpropenyl ether,

(75 naphthyl vinyl ether,

(76) neopentyl vinyl ether,

(77) 2-nitrobutyl vinyl ether,

(78) p-nitrophenyl vinyl ether,

(79) nonyl 'vinyl ether,

( 80) nonyl o-vinylphenyl ether,

(81 9,11-octadecadienyl vinyl ether,

(82) 9,12-octadecadienyl vinyl ether,

(83) 9-octadecenyl vinyl ether,

(84) octyl vinyl ether,

(8 5) pentachlorophenyl vinyl ether,

(86) 2,2,3,3,3-pentafluoropropyl vinyl ether,

(87 1- l-pentenyl) -2-hexenyl vinyl ether,

(88) 4-pentenyl trifluorovinyl ether,

(89) l-pentylhexyl vinyl ether,

(90) pentyl vinyl ether,

(91) 1 phenethyl vinyl ether,

(92) l-phenyl-p-tolyl vinyl ether,

(93) phenyl trichlorovinyl ether,

(94) phenyl o'(and p) -vinylphenyl ether,

(95) propenyl vinyl ether,

(96) propyl o vinylphenyl ether,

(97) propyl trifluorovinyl ether,

(98) thymyl vinyl ether,

(99) indanyl vinyl ether,

( 100) m(o and p) -tolyl vinyl ether,

( 101) 2,2,2-trifl-uoroethyl trifluorovinyl ether,

(102) trifiuoroethyl vinyl ether,

(103) 2,3,5 -trichlorophenyl vinyl ether,

(1041) 2,3,4-trimethyl-Lcyclohexen-l-yl-methyl vinyl et er,

( 105 trimethylnonyl vinyl ether and 106) vinyl 3,5-Xylyl ether,

yields, respectively,

(1) 11 3,21 dihydroxy 4,17(20)-cis-pregnadien-3 one 21-(1'-phenoxyethyl) ether (II),

(2) 115,21 dihydroxy 4,17(20)-cis-pregnadien-3-one 21-(1-benzyloxy-2-bromopropy1) ether (II),

(3) 11,8,21 dihydroxy 4,17(20)-cis-pregnadien-3-one 2l-(1-benzyloxyethyl) ether (II),

(4) 11,8,21 dihydroxy 4,l7(20)-cis-pregnadien-3-one 21-(1'-methoxy-2'-bromoethyl) ether (II),

(5) 115,21 dihydroxy 4,l7(20)-cis-pregnadien-3-0ne 21-(1'-ethoxy-1-bromoethyl) ether (II),

(6) 1118,21 dihydroxy 4,17 (20)-cis-pregnadien-3-one 21-(1-ethoxy-2'-bromoethyl) ether (II),

(7) 1119.21 dihydroxy 4,17(20)-cis-pregnadien-3-one 21-(1-0-tolyloxy-2-bromoethyl) ether (II),

(8) 116,21 dihydroxy 4,17(20)-cis-pregnadien-3-one 21-(1'-phenoxy-2'-bromoethyl) ether (II),

(9) 115,21 dihydroxy 4,17(20)-cis-pregnadien-3-one 21-[1-(2-butyloctyloxy)ethyl] ether (II),

(10) 113,21 dihydroxy-4,17(20)-cis-pregnadien-3-one 21-(1-butoxy-1'-phenylethyl) ether (II), etc.

Following the procedure of Example 7 but employing the corresponding trans compounds of Formula I as starting materials yields the respective trans compounds of (1) to (10) of Formula II.

EXAMPLE 8 In this example certain of the new compounds of this invention are prepared by a novel process therefor, which 13 I Pyrex tube having a medium porosity fritted disk at the bottom and a cold finger mounted at the top extending through the center of the tube to be fritted disk. Oxygen was passed through the disk at the rate of 0.5 cu. ft./hour while the tube containing the reactants was illuminated with four 15 watt fluorescent lamps. The temperature was maintained at about 15 C. throughout the 23 hours of photooxygenation. The completion of the photooxygenation was determined by noting the disappearance of the starting material (11) by TLC, employing silica gel with 30% ethyl acetate: 70% Skellysolve B. The reaction mixture was added to 400' ml. of water and the pyridine removed by steam distillation. The remaining mixture was extracted with three 125 m1. portions of methylene chloride. The combined extracts were washed with 150 ml. of 2 N hydrochloric acid and concentrated in vacuo to yield a high boiling residue. TLC of this material showed the major component to be 11l3,21-dihydroxy-4,16-pregnadien-3,20-dione ZI-tetrahydroyranyl ether (IV). A sample of pure material (IV) was obtained via column chromatography. Athough the sample remained an oil, its ultraviolet, infrared and NMR spectra proved its purity and that its structure was as predicted.

Example 10.--1 15,21-dihydroxy-4,16-pregnadien-3,20- dione 21-tetrahydropyranyl ether (IV) A solution of 16 g. (38.6 mmoles) of 1113,21-dihydroxy- 4,17(20)-cispregnadien-3-one 2l-tetrahydropyrany1 ether (II) (obtained in Example 2) and 25 mg. of rose bengal dye in 100 ml. of dry acetone was placed in a 2.5 x 56 cm. Pyrex tube having a medium porosity fritted disk at the bottom and a cold finger mounted at the top extending through the center of the tube to the fritted disk. Oxygen was passed through the disk at the rate of 0.25 cu. ft./ hour while the tube containing the reactants was illuminated with four 15 watt fluorescent lamps. The temperature was maintained at about C. throughout the 6 hours of photooxygenation. The reaction mixture containing 20u-hydroperoxy-11,8,21-dihydroxy-4,16-pregnadien-3- one 21-tetrahydropyrany1 ether (III) was added to 5.67 ml. (60 mmoles) of acetic anhydride in 10 m1. of pyridine; this was kept at about C. for about 36 hours. About 5 m1. of water was added to decompose the excess acetic anhydride and after standing for about 5 hours the solution was added to 500 ml. of benzene. The benzene solution was washed successively with 100 ml. of water, two 100 ml. portions of saturated 3 N hydrochloric acid, 100 ml. of water, two 100ml. portions of saturated sodium bicarbonate solution and finally with 100 ml. of water. The dried benzene layer was passed through magnesol (magnesium silicate) to remove the remaining dye. Concentration in vacuo afforded a high boiling residue which contained the desired 11,8,21-dihydroxy-4,1-6-pregnadien- 3,20-dione 21-tetrahydropyrany1 ether (IV).

Example 11.-113,21-dihydroxy-4,l6-pregnadien-3,20-

dione 21-tetrahydropylranyl ether (IV) A solution of crude 11,8,21-dihydroxy-4,17(20)-cispregnadien-3-one 21-tetrahydropyranyl ether (prepared from 50 g. of 11fi,21-dihydroxy-4,17(20)-cis-pregnadien- 3-one (I) in the manner of Example 1) and 80 mg. of

hematoporphyrin dye in 20.4 ml. of acetic anhydride and ml. of dry pyridine was photooxygenated for about 23 hours in an apparatus similar to that described in Examples 9 and 10. The reaction mixture was added to 400 ml. of water and the pyridine removed by steam distillation. The remaining mixture was extracted with three ml. portions of methylene chloride. The combined extracts were washed with ml. of 2 N hydrochloric acid and concentrated in vacuo to yield a high boiling residue containing 11,9,21-dihydroxy-4,16-pregnadien-3,20-dione 2 tetrahydropyranyl ether (IV).

Example 12.--l15,21-dihydroxy-4,16-pregnadien-3,20- dione 21-(1'-isobutoxyethyl) ether (IV) The product from Example 3, 115,21-dihydroxy- 4,17(20) cis pregnadien 3-one 21-(1-isobutoxyethyl) ether (II), was dissolved in 150 ml. of acetone containing 40 mg. of rose bengal dye was photooxygenated for about 23 hours in the same apparatus as described in Example 9. Then 18.3 ml. of acetic anhydride and 30 m1. of pyridine was added as the temperature rapidly increased to about 45 C. The reaction mixture was cooled to about 25 C. and kept at this temperature for about 1 hour. The excess of acetic anhydride was hydrolyzed by the addition of 20 ml. of water. The mixture was concentrated in vacuo giving a high boiling residue to which was added .600 ml. of benzene. The benzene layer was washed thoroughly with 3 N hydrochloric acid solution followed by water. Concentration of the benzene layer produced 115,21 dihydroxy-4,16-pregnadien-3,20-dione 21-(1'-isobutoxy ethyl) ether (IV) as an oil.

Example 13.--11,8,21-dihydroxy-4,16-pregnadien-3,20- dione 21-(1'-methoxyethyl) ether (IV) A 2 g. sample of 115, 21-dihydroxy-4,l7(20)-cis-pregnadien-3-one 21-(1'-methoxyethyl) ether (11) (obtained in Example 4) was photooxygenated in acetone employing procedures similar to those described in Example 9 to yield 20oz hydroperoxy 1l/3,21-dihydroxy-4,l6-pregnadien-3-one 21-(1'-methoxyethyl) ether (III) which was (without isolation) converted to 1l/3,21-dihydroxy-4,l6- pregnadien-3,20 dione 21-(1'-methoxyethyl) ether (IV).

Example 14 In this example certain of the new compounds of this invention are prepared by a novel process therefor, which is illustratively represented by the following reaction sequence:

THz-O-E H wherein 1(2), 3(4), 4(5), 5(6), 6(7), E, V, W, Y and Z have the same meaning as those given therefor following the flow-sheet in column 2.

Following the procedure of Example 9 but substituting for 11,8,21-dihydroxy-4,17(20-cis-pregnadien-3-one 21- tetrahydropyranyl ether (II) the following representative starting materials:

(1) 11 9,21-dihydroxy-4,17 (20) pregnadiene-3-one 21- tetrahydropyranyl ether (II),

(2) 21-hydroxy-4,17 (20)-pregnadien-3-1l-dione 21-(1'- isobutoxyethyl) ether (II),

(3) 11a,21-dihydroxy-4,17 (20)-pregnadien-3-one 21-(lmethoxyethyl) ether (II),

(4) 2l-hydroxy-4,6,l7 (20)-prcgnatrien-3-one 21-(1'-isopropoxyethyl) ether (II),

(5) 115-21-dihydroxy-17 (20)-pregnen-3-one 21-tetrahydrofuranyl ether (II),

(6) 35,2-dihydroxy-17 (20)-pregnene 21-(1-methoxy-1- fluoro12'2'-diehloroethyl) ether (II),

(7) 4-chloro-115,21-dihydroxy-4,17 (20) pregnadien-3- one 21-(1-phenoxy-1-fluoro-2,2-dichloroethyl) ether (8) Za-fiuoro-l15,21-dihydroxy-4,17 (20) pregnadien-3- one 21 [2,2'-dichloro-1-fiuoro-1-(2",2,2-trifluorethoxy)ethyl] ether (II),

(9) 2u-methyl-115,21-dihydroxy-4,6,17 (20)-pregnatrien- 3 one 21 [1'-(2,4"-dichlorophenoxy)ethyl] ether (II), and

(10) 21-hydroxy-2-methyl-1,4,17 (20)-pregnatrien-3-one 21-(1,2'-dichloro-1-ethoxyethyl) ether (II),

yields, respectively,

tetrahydropyranyl ether (IV),

(2) 21 hydroxy 4,16-pregnadien-3,11,20-tri0ne 21-(1'- isobutoxy ethyl) ether (IV),

(3) 11a,2l-dihydroxy-4,16-pregnadicn-3,20-dione 2l-(1'- methoxyethyl) ether (IV),

yields 20a hydroperoxy 115,21 dihydroxy-4,l6-pregnadien-3-one 21-(1-methoxy-1'-methylethy1) ether (III).

(b) 115,21-dihydroxy 4,16 pregnadien-3,20-dione 2l-(1'-methoxy-1-1nethylethy1) ether (lV).The material from (a), 20a-hydroperoxy-l15,21-dihydroxy 4,16- pregnadien 3 one 21-( l-methoxy-1-methylethyl) ether (III), in pyridine and acetic anhydride is allowed to stand at room temperature for about hours. The solution is then warmed briefly to about 60 C., cooled and water added. The resulting precipitate is extracted with ethyl acetate, washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution, dried over sodium sulfate and the liquid evaporated to give 115,21-dihydroxy 4,16 pregnadien-3,20-dione 21-(1'-methoxy-1'- 15 methylethyl) ether (IV).

4 (4)21 hydroxy-4,6,16-pregnatrien-3,20-dione 21-(1'-iso- The A --ketones (IV) of (1) to (10), above can be prepared from either the cis or trans from of the corresponding A -compounds (II) of (1) to (10).

Example 15 (a) 20st hydroperoxy 115,21-dihydroxy-4,l6-pregnadien-3-one 21-(1'-methoxy-1-methylethyl) ether (III). A 1 g. sample of l15,21-dihydroxy-4,l7 (20)-cis-pregnadien-3-one 21 (1-methoxy-l'-methylethyl) ether (11) (obtained in Example 5) in 15 ml. of dry acetone containing 15 mg. of rose bengal was photooxygenated at room temperature for about 3 hours (employing the apparatus described in Example 9) to yield 20a-hydroeroxy 115,21 dihydroxy-4,l6-pregnadien-3-one 21-(1- methoxy-1-methylethyl) ether (III).

Following the procedure of Example 15(a), but substituting 115.21 dihydroxy-4.17 (20)-trans-pregnadicn- 3on Z! T (l-methoxy-l'-mcthylethyl) other (11) also Example 16 In this example certain of the new compounds of this invention are prepared by a novel process therefor, (1) 115,21 dihydroxy 4,16-pregnadien-3,20-dione 21- 20 which is illustratively represented by the following reaction sequence:

CHz-O-E wherein 1(2), 3(4), 4(5), 5(6), 6(7), E, V, W, Y, and Z 'have the same meaning as those given therefor following the flow-sheet on page 2.

Following the procedure of Example 15(a) but substituting for 11521-dihydroxy 4,17(20) cis-pregnadien- 3-one 21-(1'-methoxy 1 methylethyl) ether (11) the following representative cis-starting materials (prepared as in U.S. Patent 2,781,343):

(1) 115,21-dihydroxy- 1 ,4,17(20)-pregnatrien-3-one 21-( l-methoxy-2-methylpropy1) ether (II),

(2) 115,21,dihydroxy-4,6,17(20)-pregnatrien-3-one Zl-(I-methoxyethyl) ether (II),

(3) 21-hydroxy-1,4,17(20)-pregnatriene-3,ll-dione ZI-tetrahydropyranyl ether (II),

(4) 21-hydroxy-4,17(20)-pregnadiene-3,1l-dione 21- (2',2-dichloro-1-fluoro-1-phenoxyethyl) ether (II),

(5) 2a-methyl-21-hydroxy-4,17(20)-pregnadiene-3,1 1-

dione 21-[1-(2",4"-dich1orophcnoxy)ethyl] ether (II),

(6) 21-hydroxy-4,l7(20)-pregnadien-3-onc 21-tetrzthydrofuranyl ether (II),

(7) 21-hydr0xy-1,4,17(20)-pregnatrien-3-one 2l-(1- dodecyloxyethyl) ether (II),

(8) 2tx-methyl-115,21-dihydr0xy-1,4,17(20)-pregnatrien- 3-one 21-(1-cyclohexyloxyethyl) ether (II),

(9) 4-fluoro-l15,2l-dihydr0xy-15a-methyl-l,4,17(20)- pregnatrien-3-one 21 1-naphthoxyethyl) ether (10) 6a,16a-dimethyl-115,21-dihydroxy-1,4,17(20) pregnatrien-3-one 2l-(1-pentachlorophenoxy ethyl) ether (II), etc.,

yields respectively,

(1) 20tz-hydroperoxy-115,21-dihydroxy-1,4,16-

pregnatrien-21-(1-methoxy-2-methylpropyl) ether (III),

(2) ZOa-hydrO eroXy-I15.2l-dihytl|'oxy-4,6,l6-

prcgnalrien-Zl-(l-methoxyethyl) ether,

The mother liquors from the compounds of (1) through above, yield a residue containing the corresponding ZOB-hydroperoxy compounds (III).

Following the procedure of Example (a) but substituting the corresponding trans starting materials (II) also yields the u-hydroperoxy steroids (III) of (1) through (10), above.

Example 17 In this example certain of the new compounds of this invention are prepared by a novel process therefor, which is illustratively represented by the following reaction sequence:

wherein 1(2), 3(4), 4(5), 5(6), 6(7), E, V, W, Y and Z have the same meanings as those given therefor following the flow-sheet in column 2.

Following the procedure of Example 15 (b) but substituting for 20a-hydroperoxy 11 3,21 dihydroxy-4,16- pregnadien-3-one 21-(1-methoxy-1'-methylethy1) ether (HI) the following representative starting materials:

yields, respectively,

(1 11 8,2 l-dihydroxy- 1,4, 1 6-pre gnatrien-3,20-dione 21-(1-isobutoxyethyl) ether (IV),

(2) 11B,21-dihydroxy-4,6,16-pregnatrien-3,20-dione 21- 1'-methoxyethyl) ether (IV),

(3) 21-hydroxy-1,4,16-pregnatrien-3,11,20-trione 21-tetrahydropyranyl ether (IV),

(4) 2l-hydroxy-4,16-pregnadien-3,l1,20-trione 21-(2',2'-

dichloro-l-fluoro-1'-phenoxyethyl) ether (IV),

(5) 21-hydroxy-4,16-pregnadien-3,11,20-trione 21- 1'- (2,4"-dichlorophenoxy)ethyl] ether (IV),

(6) 21-hydroxy-4,l6-pregnadien-3,20-dione 21-tetrahydrofuranyl ether (IV),

(7) 2l-hydroxy-1,4,16-pregnatrien-3,20-dione 21-(1-dodecyloxyethyl) ether (IV),

( 8) 1118,2l-dihydroxy-1,4,16-pregnatrien-3,20-dione 21-(1-eicosyloxyethyl) ether (IV),

(9) 3,8,2l-dihydroxy-16-pregnene-20-one 21-(1-heptyloxyethyl) ether (IV),

(10) 11,8,21-dihydroxy-4,15a-methyl-1,4,16-pregnatriene- 3,20-dione 21-(1-naphthoxyethyl) ether (IV), etc.

Following the procedure of Example 15 but substituting the corresponding ZOB-hydroperoxides (III) for the 20u-hydroperoxy starting materials (III) in (1) to (10), above, also yields the 20-keto-products of Formula IV in (1) to (10), above.

Example 18.1 1/3-21-dihydroxy-4,16-pregnadiene- 3,20-dione (V) The product from Example 9, 11B,2l-dihydroxy-4,l6- pregnadien-3,20-dione ZI-tetrahydropyranyl ether (IV), was dissolved in 250 ml. of methanol and to this 250 mg. of p-toluenesulfonic acid was added. After standing at room temperature for about 45 minutes, TLC showed the exchange of the tetrahydropyranyl ether group for that of hydroxyl was complete. After the addition of 2 ml. of diethylamine, the methanol was removed in vacuo. The residue was taken up in 200 ml. of benzene for crystallization. After standing at room temperature for about 16 hours, the solids were collected by filtration to give, after drying, 30.64 g. [58.9% yield from starting material (1)] of 11,6,21-dihydroxy-4,16-pregnadien-3,20-dione (V), melting at 154 to 159 C. An analytical sample of this material was obtained by recrystallization from benzene and had a melting point of 157 to 158.5 C.,

W 24.1 m (e =22,900

Example 19.1 113,21-dihydroxy-4, lfi-pregnadien- 3,20-dione (V) The product residue obtained in Example 10, 1113,21- dihydroxy 4,16 pregnadien 3,20 dione ZI-tetrahydropyranyl ether (IV), was dissolved in 60 ml. of benzene and 15 ml. of methanol. To this 1 drop of concentrated hydrochloric acid was added with stirring. After about 1 hour an additional drop of hydrochloric acid was added. After stirring at about 25 C. for about 16 hours, the solution was concentrated to 40 ml. by distillation. Then 25 ml. of Skellysolve B was added. Filtration gave 8.87 g. of crude product V. Recrystallization from a mixture of benzene and Skellysolve B gave 6.24 g. (44% yield) 19 of 115,21-dihydroxy-4,16-pregnadien-3,20-dione (V), melting at 157.2 to 159 C. An analytical sample was obtained by recrystallization from benzene which melted at 157 to 158.5 C. and with x at 241 m1. (6 =22,900)

Example 20.1 15,21-dihydroxy-4,16-preguadien- 3,20-dione (V) The product residue obtained in Example 11, 115,21- dihydroxy 4,16 pregnadien 3,20 dione 21-tetrahydropyranyl ether (IV), was dissolved in 250 ml. of methanol and 250 ml. of p-toluenesulfonic added. After standing at room temperature for about 45 minutes, 2 ml. of diethylamine was added and the solution concentrated in vacuo. The residue was taken up in 250 ml. of benzene. After standing, 30.6 g. (59% yield) of 11,6,21-dihydroxy- 4,16-pregnadien-3,20-dione (V) melting at 154 to 159 C. was collected by filtration.

Example 21.-1.1,B,21-dihydroxy-4,l-pregnadien- 3,20-dione (V) Example 22.--1113,21-dihydroxy-4,16-pregnadien- 3,20-dione (V) The product obtained in Example 13, 11,8,21-dihydroxy- 4,l6-pregnadien-3,20-dione 21-(1'-methoxyethyl) ether (IV), was treated in the same manner as the 1113,21-dihydroxy-4,16-pregnadien-3,20-dione 21-tetrahydropyranyl ether (IV) employed as starting material in Example 18. This procedure yielded pure 11p,21-dihydroxy-4,16- pregnadien-3,20-dione (V).

Example 23 .--1 1,8,21-dihydroxy-4,16-pregnadien- 3,20-dione (V) The product obtained in Example 15(b), namely, 113,21 dihydroxy 4,16 pregnadien-3,20-dione 21-( lmethoxy-1'-methylethyl) ether (IV), was treated with methanol and p-toluenesulfonic acid in accordance with the procedure of Example 18 to yield pure 11;3,2l-dihydroxy-4,16-pregnadien-3,20-dione (V).

Example 24 In this example certain of the new compounds of Formula IV of this invention are converted to those of Formula V by the following reaction sequence:

20 wherein 1(2), 3(4), 4(5), 5(6), 6(7), E, V, W, Y and Z have the same meaning as those given therefor fol lowing the flow-sheet in column 2.

Following the procedure of Example 18 but substituting for 1113,21-dihydroxy-4,16-pregnadien-3,20-dione 21-tetrahydropyranyl ether (IV) the following representative starting materials:

(1) 11,8,2l-dihydr0xy-l,4,16-pregnatriene-3,20-dione 21-tetrahydrofuranyl ether (IV),

(2) 6a-methyl-3a,115,2l-trihydroxy-l6-pregnene-20-one 2l-[l'-(2,4"-dichlorophenoxylethyl] ether (IV),

(3) 9a-flu0ro-115,21-dihydroxy-1,4,6,16-pregnatetraen- 3,20-dione 21-(1'-dodecyloxyethyl) ether (IV),

(4) 11b,21-dihydroxy-5,16-pregnadiene-3,20-dione 3-ethylene ketal 21-(1-phenoxyethyl) ether (IV),

(5) 16B-methyl-1 15,21-dihydroxy-4,16-pregnadien-3,20-

dione 2l-(1-naphthoxyethyl) ether (IV), etc.,

yields respectively,

(1) 11B,2l-dihydroxy-1,4,16-pregnatrien-3,20-dione (V),

(2) 6a-methyl-3a,l15,2l-trihydroxy-16-pregnen-20-one (3) 9a-fl110r0-1 1fi,21-dihydroxy-1,4, l6-pregnatetraen- 3,20-dione (V),

(4) 116,21-dihydroxy-5,16-pregnadien-3,20-dione 3-ethylene ketal (V),

(5) 16,6-methyl-11/3,21-dihydroxy-4,16-pregnadien-3,20-

dione (V), etc. I claim: 1. Compounds of the formula wherein the 1(2), 3(4), 4(5), 5(6) and 6(7)-carbon atom linkages are selected from the group consisting of single bonds and double bonds; is a generic expression denoting ozand ti-bonds and mixtures thereof; E is selected from the group consisting of wherein R is selected from the group consisting of alkyl, haloalkyl, nitroalkyl, alkenyl, cycloalkyl, aryl, aralkyl, haloaryl haloarylkyl and nitroaryl of from 1 to 24 carbon atoms, inclusive; and R R and R have the same meaning as R and in addition hydrogen; V is selected from the group consisting of hydrogen and hydroxy, with the proviso that V is not present when the 4(5)- or 5(6)-carbon atom linkage is a double bond; W is selected from the group consisting of hydrogen, methyl, chlorine and fluorine; Y is selected from the group consisting of the a-hydroxymethylene radical the fl-hydroxymethylcne radical the u-acyloxymethylene radical wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, the ,B-acyloxymethylene radical wherein n is selected from the group consisting of zero and the integers one and two and R is selected from the group consisting of hydrogen and a lower-alkyl radical containing from one to six carbon atoms, inclusive; when Y is a carbonyl radical the 1(2), 4(5), 6(7) and 9(1l)- carbon atom linkages are selected from the group consisting of single and double bonds; when Y is other than a carbonyl radical the 1(2), 3(4), 4(5), 5(6), 6(7) and 9(ll)-carbon atom linkages are selected from the group consisting of single and double bonds; Z is selected from the group consisting of themethylene radical CH the a-hydroxymethylene radical, the S-hydroxymethylene radical, the carbonyl radical and when W is selected from the group consisting of chlorine and fluorine, Z is additionally selected from the group consisting of chloromethylene and fluoromethylene; Z and W at the 9-position together constitute a 9(11)-double bond.

2. A compound in accordance with claim 1, namely, 20a-hydroperoxy 115,21 dihydroxy-4,l6-pregnadien- 3-one 21- tetrahydropyranyl ether of the formula H CHz-O 4. A compound in accordance with claim 1, namely, 20a-hydroperoxy 1118,21 dihydroxy 4,16-pregnadien- 3-one 21-(1-isobutoxyethyl) ether.

5. A compound in accordance with claim, 1, namely, 20a-hydroperoxy-11p,21 dihydroxy 4,16-pregnadien-3- one 2l-(1'-ethoxy-1-methylethyl) ether.

6. A compound in accordance with claim 1, namely, 20oz hydroperoxy 115,21 dihydroxy 4,16-pregnadien- 3-one 21-(l-methoxyethyl) ether.

7. A process for the production of a compound of claim 1 of the Formula IV wherein the 1(2), 3(4), 4(5), 5(6), and 6(7)-carbon atom linkages are selected from the group consisting of single bonds and double bonds; is a generic expression denoting aand fi-bonds and mixtures thereof; E is selected from the group consisting of wherein R is selected from the group consisting of alkyl, haloalkyl, nitroalkyl, alkenyl, cycloalkyl, aryl, aralyl, haloaryl, haloaralkyl and nitroaryl of from 1 to 24 carbon atoms, inclusive; and R R and R have the same meaning as R and in addition hydrogen; V is selected from the group consisting of hydrogen and hydroxy with the proviso that V is not present when the 4(5)- or 5(6)- carbon atom linkage is a double bond; W is selected from the group consisting of hydrogen, methyl, chlorine and fluorine; Y is selected from the group consisting of the a-hydroxymethylene radical the p-hydroxymethylene radical the a-acyloxymethylene radical OAc 0* wherein Ac is the acyl radical of an organic carboxylic acid containing from one to twelve carbon atoms, inclusive, the fi-aceyloxymethylene radical OAc (W H 23 wherein Ac has the same meaning as above, the acyloxymethylidyne radical COAc) wherein Ac has the same meaning as above, the alkoxy'methylidyne radical COR) wherein R is a lower-alkyl radical of from one to six carbon atoms, inclusive, the carbonyl radical C=O) and an alkylene ketal radical of the formula wherein n is selected from the group consisting of zero and the integers one and two and R is selected from the group consisting of hydrogen and a lower-alkyl radical containing from one to six carbon atoms, inclusive; when Y is a carbonyl radical the 1(2), 4(5), 6(7) and 9(1l)- carbon atom linkages are selected from the group consisting of single and double bonds; when Y is other than a carbonyl radical the 1(2), 3(4), 4(5), (6), 6(7) and 9(ll)-carbon atom linkages are selected from the group consisting of single and double bonds; Z is selected from the group consisting of the methylene radical CH the a-hydroxymethylene radical, the fl-hydroxymethylene radical, the carbonyl radical and when W is selected from the group consisting of chlorine and fluorine, Z is additionally selected from the group consisting of chloromethylene and fluoromethylene; Z and W at the 9-position together constitute a 9(1l)-double bond, which comprises subjecting to dehydration at the 20-position a corresponding compound of the Formula III wherein 1(2), 3(4), 4(5), 5(6), 6(7), E, V, W, Y and Z have the same meaning as above.

8. A process in accordance with claim 7 for the production of l1,8,21-dihydroxy-4,16-pregnadien-3,20-dione 21- tetrahydropyranyl ether (IV) which comprises subjecting to dehydration at the 20-position 20a-hydroperoxy-1 1 8,21- dihydroxy-4,1G-pregnadien 3 one ll-tetrahydropyranyl ether (III).

9. A process in accordance with claim 7 for the production of 1113,21dihydroxy-4,l6-pregnadien-3,20-dione 21- tetrahydropyranyl ether IV) which comprises subjecting to dehydration at the 20-position with a base 20ot-hydroperoxy-l113,21-dihydroxy-4,l6-pregnadien-3-one 2l-tetrahydropyranyl ether (III).

10. A process in accordance with claim 7 for the production of 1113,21-dihydroxy-1,4,16-pregnatriene-3,20-dione 21-tetrahydropyranyl ether (IV) which comprises subjecting to dehydration at the 20-position 20ot-hydroperoxy- 1119,21 dihydroxy 1,4,16 pregnatrien 3 one 21 tetrahydropyranyl ether (III).

11. A process in accordance with claim 7 for the production of 11,8,21-dihydroxy-l,4,16-pregnatrien-3,20-dione Zl-tetrahydropyranyl ether (IV) which comprises subsubjecting to dehydration at the 20-position with a base 20a hydroperoxy 115,21 dihydroxy 1,4,16 pregnatrien-3-one 2l-tetrahydropyranyl ether (III).

12. A process for the production of a compound of the Formula IV wherein the 1(2), 3(4), 4(5), 5(6) and 6(7)-carbon atom linkages are selected from the group consisting of single bonds and double bonds; is a generic expression denoting aand fi-bonds and mixtures thereof; E is selected from the group consisting of wherein R is selected from the group consisting of alkyl, haloalkyl, nitroalkyl, alkenyl, cycloalkyl, aryl, aralkyl, haloaryl, haloaralkyl and nitroaryl of from 1 to 24 carbon atoms, inclusive; and R R and R have the same meaning as R and in addition hydrogen; V is selected from the group consisting of hydrogen and hydroxy with the proviso that V is not present when the 4(5)- or 5(6)- carbon atom linkage is a double bond; W is selected from the group consisting of hydrogen, methyl, chlorine and fluorine; Y is selected from the group consisting of the ot-hydroxymethylene radical the p-hydroxymethylene radical OH k i H the a-acyloxymethylene radical wherein Ac is the acyl radical of an organic carboxylic acid containing from one to twelve carbon atoms, inclusive, the [i-acyloxymethylene radical wherein Ac has the same meaning as above, the acyloxymethylidyne radical COAc) wherein Ac has the same meaning as above, the alkoxymethylidyne radical (BC-OR) wherein R is a lower-alkyl radical of from one to six carbon atoms, inclusive, the carbonyl radical O=O) and an alkylene ketal radical of the formula 0(C1'I2)., R

wherein n is selected from the group consisting of zero and the integers one and two and R is selected from the group consisting of hydrogen and a loweralkyl radical containing from one to six carbon atoms, inclusive; when Y is a carbonyl radical the 1(2), 4(5), 6(7) and 9(11)- carbon atom linkages are selected from the group consisting of single and double bonds; when Y is other than a carbonyl radical the 1(2), 3(4), 4(5), (6), 6(7) and 9(11)-carbon atom linkages are selected from the group consisting of single and double bonds; Z is selected from the group consisting of the methylene radical OH the a-hydroxymethylene radical, the fi-hydroxytmethylene radical, the carbonyl radical and when W is selected from the group consisting of chlorine and fluorine, Z is additionally selected from the group consisting of chloromethylene and fluoromethylene; Z and W at the 9-position together constitute a 9(11)-double bond, which comprises ('1) subjecting to photosensitized oxygenation a corresponding compound of the Formula II ripe-1: Z,

wherein V, W, and Z have the same meaning as above, to produce a corresponding compound of the Formula III Gila-(FE wherein 1(2), 3(4), 4(5), 5(6), 6(7), E, V, W, Y, and Z have the same meanings as above, and (2) subjecting a thus produced corresponding compound of Formula III to dehydration at the 20-position to yield a corresponding compound of Formula IV, above.

13. A process in accordance with claim 12 for the production of 115,21 dihydroxy-4,l6-pregnadiene-3,20- dione 21-tetrahydropyranyl ether (IV) which comprises (1) subjecting 11/3, 2l-dihydroxy-4,17(20)-cis-pregnadien- 3-0ne 21-tetrahydropyranyl ether (II) to photosensitized oxygenation to yield 20a-hydroperoxy-l15,21-dihydroxy- 4,16-pregnadien-3-one 21-tetrahydropyranyl ether (III) and (2) subjecting the thus produced compound (III) to dehydration at the 20-position to yield 11,8,21-dihydroxy- 4,16-pregnadiene-3,20-dione 21-tetrahydropyranyl ether- 14. A process in accordance with claim 12 for the production of 11 3,21 dihydroxy-4,16-pregnadiene-3,20- dione 2l-tetrahydropyranyl ether (IV) which comprises 1 treating 1lfl,21-dihydroxy-4, 17 (20) -cis-pregnadien-3- one 21-tetrahydropyranyl ether (II) with oxygen in the presence of hematoporphyrin during irradiation with fluorescent light to yield 20a-hydroperoxy-1113,21-dihydroxy-4,16-pregnadien-3-one Zl-tetrahydropyranyl ether (III) and (2) dehydrating at the 20-position the thus produced compound (III) by treatment with a base to yield 1113,21 dihydroxy 4,l6-pregnadien-3,20-dione 21- tetrahydropyranyl ether (IV).

15. A process in accordance with claim 12 for the production of 11fl,21-dihydroxy-1,4,16-pregnatriene-3,20- dione 2l-tetrahydropyranyl ether (IV) which comprises (1) subjecting 115,21 dihydroxy 1,4,l7(20) cis-pregnatrieri-S-one Z-tetrahydropyranyl ether (II) to photosensitized oxygenation to yield 20a-hydr0peroxy-ll,8,2ldihydroxy-1,4,l6-pregnatrien-3-one 2l-tetrahydropyranyl ether (III) and (2) subjecting the thus produced compound (III) to dehydration at the 20-position to yield 113,21 dihydroxy-1,4,16-pregnatrien-3,20-dione 21-tetrahydropyranyl ether (IV).

16. A process in accordance with claim 12 for the production of 11 8,21-dihydroxy-l,4, l 6-pregnatriene-3,20- dione 2l-tetrahydropyranyl ether (IV) which comprises (1) treating 113,21 dihydroxy 1,4,17(20) cis-pregnatrien-B-one 2l-tetrahydropyranyl ether (II) with oxygen in the presence of hematoporphyrin during irradiation with fluorescent light to yield ZOa-hydroperoxy-llfl, 21-dihydroxy-4,16-pregnadien-3-one (III) and (2) dehydrating at the 20-position the thus produced compound (III) by treatment with a base to yield 115,21-dihydroxy- 1,4,16-pregnatriene-3,ZO-dione 21-tetrahydropyranyl ether 17. A process for the production of a compound of the Formula IV.

Tflz-O-E C-O wherein 1(2), 3(4), 4(5), 5(6), and 6(7)-carbon atom linkages are selected from the group consisting of single bonds and double bonds; -is a generic expression denoting aand fi-bonds and mixtures thereof; E is selected from the group consisting of wherein R is selected from the group consisting of alkyl, haloalkyl, nitroalkyl, alkenyl, cycloalkyl, aryl, aralkyl, haloaryl, haloaralkyl and nitroaryl of from 1 to 24 carbon atoms, inclusive; and R R and R have the same meaning as R and in addition hydrogen; V is selected from the group consisting of hydrogen and hydroxy with the proviso that V is not present when the 4(5)- or 5(6)-carbon atom linkage is a double bond; W is selected from the group consisting of hydrogen, methyl, chlorine and fluorine; Y is selected from the group consisting of the a-hydroxymethylene radical the B-hydroxymethylene radical the a-acyloxymethylene radical wherein Ac is the acyl radical of an organic carboxylic acid containing from one to twelve carbon atoms, inclusive, the ,H-acyloxymethylene radical wherein Ac has the same meaning as above, the acyloxymethylidyne radical COAc) wherein Ac has the same meaning as above, the alkoxymethyldyne radical (2COR) wherein R is a lower-alkyl radical of from one to six carbon atoms, inclusive, the carbonyl radical C=O) and an alkylene ketal radical of the formula wherein n is selected from the group consisting of zero and the integers one and two and R is selected from the group consisting of hydrogen and a lower-alkyl radical containing from one to six carbon atoms, inclusive; when Y is a carbonyl radical, the 1(2), 4(5), 6(7) and 9(ll)- carbon atom linkages are selected from the group consisting of single and double bonds; when Y is other than a carbonyl radical, the 1(2), 3(4), 4(5), 5(6), 6(7) and 9(ll)-carbon atom linkages are selected from the group consisting of single and double bonds; Z is selected from the group consisting of the methylene radical, CH

the u-hydroxymcthylene radical, the ,B-hydroxymethylene in ro-K wherein 1(2), 3(4), 4(5), 5(6), 6(7), E, V, W, Y and Z have the same meaning as above, to produce a corresponding compound of the Formula III wherein 1(2), 3(4), 4(5), 5(6), 6(7), E, V, W, Y and Z have the same meaning as above, and a thus produced corresponding compound of Formula III, without isolation from the reaction mixture, is dehydrated at the 20-position to yield a corresponding compound of Formula IV above.

23 18. A process for the production of a compound of the Formula V Clo the S-hydroxymethylene radical the a-acyloxymethylene radical wherein Ac is the acyl radical of an organic carboxylic acid containing from one to twelve carbon atoms, inclusive, the fi-acyloxymethylene radical wherein Ac has the same meaning as above, the acyloxymethylidyne radical COAc) wherein Ac has the same meaning as above, the alkoxymethylidyne radical COR) wherein R is a lower-alkyl radical of from one to six carbon atoms, inclusive, the carbonyl'radical C O) and an alkylene ketal radical of the formula O(CH2)n R O-(CH2)n \R' wherein I1 is selected from the group consisting of zero and the integers one and two and R is selected from the group consisting of hydrogen and a lower-alkyl radical containing from one to six carbon atoms, inclusive; when Y is a carbonyl radical the 1(2), 4(5), 6(7) and 9(ll)- carbon atom linkages are selected from the group consisting of single and double bonds; when Y is other than a carbonyl radical the 1(2), 3(4), 4(5), 5(6), 6(7) and 9(1l)-carbon atom linkages are selected from the group consisting of single and double bonds; X is selected from the group consisting of the methylene radical CH the a-hydroxymethylene radical, the fl-hydroxymethylene radical, the carbonyl radical and when W is selected from the group consisting of chlorine and fluorine, Z is additionally selected from the group consisting of chloromethylene and fluoromethylene; Z and W at the 9-position together constitute a 9(1 1)-double bond, which comprises:

(1) treating a corresponding compound of the Formula I wherein 1(2), 3(4), 4(5), 6(7), V, W Y and Z have the same meaning as above, with a vinyl ether in an acid medium to produce a corresponding compound of the Formula II wherein E is selected from the group consisting of wherein R is selected from the group consisting of 3 30 wherein E: V, W, Y and Z have the same meaning as above;

(3) subjecting a thus produced corresponding compound of Formula III to dehydration at the 20-position to yield a corresponding compound of the Formula IV wherein V, W, Y and Z have the same meaning as above;

(4) hydrolyzing at the 21-position a thus produced corresponding compound of Formula IV to yield a corresponding compound of Formula V, above.

19. A process in accordance with clainl 18 wherein the compound of Formula I is 11B,21-dihydroxy-4,17 (20)- cis-pregnadien-3-one, the compound of Formula II is 1 15,2 1-dihydroxy-4, 17 (20) -cis-pregnadien-3-one 2 l-tetrahydropyranyl ether, the compound of Formula III is 2000- hydroperoxy-I1,8,21-dihydroxy-4,16-pregnadien-3-one 21- tetrahydropyranyl ether, the compound of Formula IV is 11fl,21 dihydroxy-4,16-pregnadien-3,2'0-dione 21-tetrahydropyranyl ether and the compound of Formula V is 1 1,9,21-dihydroxy-4,16-pregnadien-3,20-dione.

20. A compound in accordance with claim 1, namely, 20a hydroperoxy 115,21 dihydroxy-4,16-pregnadien-3- one 21- 1 '-methoxy-1'-methylethyl) ether.

References Cited UNITED STATES PATENTS 3,082,219 3/ 1963 Slates et al 260397.3 3,116,304 12/1963 Taub et a1. n 260397.45 3,280,157 10/ 1966 Legatt et a1. 260397.4 3,281,415 10/1966 Schneider et al. 260239.55 3,062,846 11/1962 Fried 260397.4 3,376,292 4/1968 Beard et a1. 260239.5

OTHER REFERENCES Fieser et a1.: Steroids, pp. 235-36 (1959).

HENRY A. FRENCH, Primary Examiner U.S. Cl. X.R. 

